# Human ABC and SLC Transporters: The Culprit Responsible for Unspecific PSMA-617 Uptake?

## TL;DR

This study investigates whether ABC and SLC transporters are responsible for the uptake and toxicity of a cancer treatment drug in salivary glands and kidneys.

## Contribution

The study demonstrates that ABC and SLC transporters are not involved in the uptake or toxicity of [177Lu]Lu-PSMA-617 and [225Ac]Ac-PSMA-617.

## Key findings

- [177Lu]Lu-PSMA-617 and [225Ac]Ac-PSMA-617 are not substrates of ABC and SLC transporters.
- ABC and SLC transporters do not play a central role in the uptake or toxicity of the drug in salivary glands and kidneys.
- The findings suggest alternative mechanisms for drug retention and toxicity.

## Abstract

[177Lu]Lu-PSMA-617 has recently been successfully approved by the FDA, the MHRA, Health Canada and the EMA as Pluvicto®. However, salivary gland (SG) and kidney toxicities account for its main dose-limiting side-effects, while its corresponding uptake and retention mechanisms still remain elusive. Recently, the presence of different ATP-binding cassette (ABC) transporters, such as human breast cancer resistance proteins (BCRP), multidrug resistance proteins (MDR1), multidrug-resistance-related proteins (MRP1, MRP4) and solute cassette (SLC) transporters, such as multidrug and toxin extrusion proteins (MATE1, MATE2-K), organic anion transporters (OAT1, OAT2v1, OAT3, OAT4) and peptide transporters (PEPT2), has been verified at different abundances in human SGs and kidneys. Therefore, our aim was to assess whether [177Lu]Lu-PSMA-617 and [225Ac]Ac-PSMA-617 are substrates of these ABC and SLC transporters. For in vitro studies, the novel isotopologue ([α,β-3H]Nal)Lu-PSMA-617 was used in cell lines or vesicles expressing the aforementioned human ABC and SLC transporters for inhibition and uptake studies, respectively. The corresponding probe substrates and reference inhibitors were used as controls. Our results indicate that [177Lu]Lu-PSMA-617 and [225Ac]Ac-PSMA-617 are neither inhibitors nor substrates of the examined transporters. Therefore, our results show that human ABC and SLC transporters play no central role in the uptake and retention of [177Lu]Lu-PSMA-617 and [225Ac]Ac-PSMA-617 in the SGs and kidneys nor in the observed toxicities.